FDA细胞治疗临床试验监督

1、FDA Oversight of Cell Therapy Clinical Trials,Celia Witten, Ph.D., M.D. Office Director, Office of Cellular, Tissue, and Gene Therapies CBER/FDA ISSCR/CIRM/ISCT Workshop June 15, 2010 San Francisco, California,2,FDA Organization,Office of the Commissioner Office of Combination Products CBER (Center

2、for Biologics Evaluation and Research): vaccines, blood and blood products, human tissue/tissue products for transplantation, cell therapy, gene therapy, donor screening tests for blood and tissue safety, devices CDRH (Center for Devices and Radiological Health): devices for treatment, implants, dia

3、gnostic devices CDER (Center for Drug Evaluation and Research): drugs, monoclonal antibodies, therapeutic proteins) CVM CFSAN NCTR,3,OCTGT Products,Cellular therapies Tumor vaccines and immunotherapy Gene therapies Tissue and tissue based products Xenotransplantation products Combination products De

4、vices used for cells/tissues Donor screening tests (for use with cadaveric blood samples),4,The “Tissue Rules”(21 CFR 1271, Effective May 25, 2005),5,21 CFR Part 1271,These three rules form the platform for regulation of all human cells, tissues, and cellular and tissue-based products (HCT/Ps) For c

5、ertain HCT/Ps (“361 HCT/Ps”), these regulations comprise the sole regulatory requirements For HCT/Ps regulated as drugs, devices, and/or biological products, the new tissue regulations supplement other requirements (GMP, QSR),6,Stem Cell-Based Products,Fit regulatory definitions of the following: Hu

6、man cells, tissues, or cellular and tissue based products (HCT/P) (21 CFR 1271.3(d) Biologics (PHS Act) Drugs (FDC Act) Cell therapy Gene therapy- when genetic material is transferred to cells ex vivo,7,Evolution of Stem Cell Field,Cell therapy and gene therapy products and therefore stem cell produ

7、cts- do not lend themselves to a “one size fits all” concept of product development and regulation Regulations set framework of criteria that must be fulfilled: safety, identity, purity, potency, and clinical efficacy Flexibility in how to fulfill the criteria,8,Examples of Safety Concerns for Stem

8、Cells,Defining the intended mode of action Characterization of the product, including potency Cell differentiation to undesired cell types Cell migration/trafficking to nontarget site(s) Potential uncontrolled cell proliferation or tumorigenicity Immunogenicity Graft-vs-host effects Interactions wit

9、h devices, other tissues or drugs in vivo For gene-modified cells Potential uncontrolled biological activity of the transgene Alteration of expression of the nontransgenes Insertional mutagenesis,9,Review Decision,CMC,Clinical,Pharm/Tox,Project Manager,Statistics,Epidemiology,Compliance,REVIEW OFFIC

10、E,CBER,FDA,OUTSIDE CONSULTANT,Product Quality,Scientific Expert Product expert Clinical specialist Methodology expert,Patient Advocate,Scientific Expert (SGE),Policy Expert Orphan products Ethicist Animal rule,FDA Review Team,Basic Review Team,Extended Review Team,Potential Consults or Collaborators

11、,Advisory Committee,Potential Consults,10,Examples of CMC Issues,Controls to prevent transmission of infection from the donor or introduction of infectious agents during cell processing Donor Testing and screening for relevant communicable diseases Autologous donors recommended but not required Allo

12、geneic donors must comply with 21 CFR 1271 Subpart C HCT/P donor screening is medical history interview, physical assessment and medical record review HCT/P donors are tested using FDA approved or cleared donor screening tests Cell banks- adventitious agent testing extended 9/05 to 9/2010 Over time,

13、 “clusters” of specific areas of interest were developed for more targeted information exchanges With EMA product scope enlargement to include tissue engineering with cell and gene therapies (“advanced therapeutic medicinal products” ATMPs), ATMP “cluster” initiated 2008,27,FDA-EMA ATMP “Cluster”,Re

14、gular teleconferences to share thinking on regulatory approaches, both general and specific issues Information sharing on draft documents Engage reciprocally in workshops and advisory committees, working parties,28,Regulatory Exchanges,OCTGT has hosted on limited basis regulatory colleagues, Fall of 2009: EMA ATMP expert Japan Pharmaceutical and Medical Device Agency (PMDA) cell therapy expert Additional exchanges planned for Fall of 2010 OCTGT experts routinely respond to foreign regulatory inquiries, calls for assistance, both through written communication,